IMPAHCT-FUL: A Long-Term Extension, Multi-Center Safety Study of AV-101 in Subjects With Pulmonary Arterial Hypertension (PAH) Who Have Completed Study AV-101-002

Data from the REVEAL registry demonstrate that, from the time of diagnostic
right heart catheterization and even with treatment, patients with PAH had 1-,
3-, 5-, and 7-year survival rates of 85%, 68%, 57%, and 49%, respectively
(McGoon and Miller, 2012). This reflects the serious nature of the disease and
the need for alternative PAH treatments with new mechanisms of action that
directly target the proliferative nature of the vasculopathy, with the ultimate
goal being to halt or reverse disease progression.

Clinical efficacy of oral imatinib mesylate in the treatment of PAH was
observed in Functional Class II-IV patients in the Phase 3 IMPRES trial, in
which the primary endpoint, six minute walk distance (6MWD), as well as
secondary endpoints measuring pulmonary vascular resistance (PVR), mean
pulmonary arterial pressure (mPAP), cardiac output (CO), and N-Terminal
Prohormone-B Natriuretic Peptide (NT-proBNP) all showed statistically
significant and therapeutically relevant improvements on top of the maximal
standard of care (Hoeper et al., 2013). However, oral imatinib was not well
tolerated and further clinical development was halted.

At therapeutic concentrations, imatinib is an inhibitor of the Abelson murine
leukemia viral oncogene homolog (ABL), Colony Stimulating Factor 1 Receptor
(CSF1R), KIT Proto-Oncogene Receptor Tyrosine Kinase (cKIT), Discoidin Domain
Receptor (DDR), Lymphocyte-Specific Protein Tyrosine Kinase (LCK) and
Platelet-derived growth factor receptor (PDGFR) kinases (Davis et al., 2011).
Signaling through each of these kinases has been implicated in histopathologic
remodeling in PAH including PDGFR mediated proliferation and apoptotic
resistance of vascular smooth muscle and endothelial cells, KIT expression
directly in the vasculature and its influence on precursor cells, fibrotic
signaling and recovery mediated by DDR and ABL, as well as immune dysregulation
via LCK, CSF1R and KIT (Schermuly et al., 2005; Montani 2011; Rojo et al.,
2019; Leitinger et al., 2014; and Rossy et al., 2012). Due to its
anti-proliferative effects, imatinib has the potential to be a
disease-modifying therapy for PAH.

Given the demonstrated clinical efficacy of oral imatinib in PAH, Aerovate is
developing a dry powder inhaled imatinib, AV-101, to target the delivery of
imatinib to the diseased organ, the lungs. Inhaled administration of AV-101 is
expected to provide rapid local exposure of respiratory tissue to imatinib with
a lower dose and lower systemic exposure compared to Gleevec® oral tablets.
Aerovate expects that inhaled AV-101 administration will result in a more
favorable benefit/risk profile than that observed with oral Gleevec
administration. Therefore, subjects who successfully complete the 24-week
placebo-controlled trial (AV-101-002) will be offered the opportunity to
continue into this long-term extension (LTE) study.

The objective of the study is to establish the long-term safety and
tolerability of AV-101. The long-term effects of AV-101 on efficacy measures
will also be assessed.

Study AV-101-003 is a long-term extension (LTE) follow up study where
recruitment of subjects will continue as the parent study (AV-101-002)
progresses from Phase 2b to Phase 3. Subjects who were on placebo in Phase 2b
and the Intermediate Part of the study who enroll in the LTE study will be
re-randomized to one of the 3 active AV-101 doses until such time as the
optimal dose has been selected. Once the optimal dose of AV-101 has been
selected, all subjects will be transitioned to the optimal dose while they
continue in the LTE, and subjects completing the Intermediate Part or parent
study Phase 3 will enroll into the LTE study at the optimal dose.

Subjects enrolling into the LTE study will be closely followed for the first 24
weeks given that those who transition from placebo will be receiving AV-101 for
the first time. Study visits will be every 3 months after completing the first
24-week period. Investigators and subjects will remain blinded to the
randomization in the parent study until the optimal dose has been selected for
the Phase 3 part in AV-101-002.

Subjects will be followed by the Investigator according to clinical practice,
with formal (per protocol) assessments conducted at the Screening/Baseline and
at other protocol Clinic Visits. Study visits will occur at Screening/Baseline,
Weeks 1 (phone), 4, 8, (phone) 12, 16 (phone), week 20 (phone) and 24. After
the Week 24 visit subjects will return to the clinic every 12 weeks for study
assessments. There will be a 4-week follow up by telephone after the subject*s
End of Treatment (EOT) Visit.
Week 20 phone visit is only for females of childbearing potential as the main
purpose is to provide a reminder to perform home pregnancy testing.

If a subject withdraws consent, they should return for an ED Visit as soon as
possible following the last dose and they should have a Safety Follow-Up (FU)
Visit 4 weeks after the ED Visit. Subjects will then be contacted for Vital
Status every 24 weeks after the Safety Follow Up Visit by telephone until study
completion.

Test Product, Dose, and Mode of Administration:
Capsules of AV-101 inserted into a dry powder inhaler device for administration
to subjects* lungs by inhalation.
Subjects entering the LTE study from the Phase 2b and Intermediate Parts of
AV-101-002: Capsule strength: 5 mg, 17.5 mg, or 35 mg AV-101. Administered
Doses (2 capsules): 10 mg, 35 mg, or 70 mg AV-101, BID.
Subjects entering the LTE study from the Phase 3 Part of AV-101-002: AV-101
optimal dose, BID.

The burden and risks mainly consist out of extra time spent and the subject may
suffer from the measurements during the study. No serious adverse events were
reported by healthy volunteers who were administered AV-101 in a Phase 1 study.